1. Field of the Invention
This invention related to a new FK-506 antagonist agent, a C-21-hydroxy-FR-900520, a novel fermentation process for its production, utilizing the novel microorganism Streptomyces hygroscopicus (MA 6832), ATCC No. 55166. The process involves culturing the microorganism in the presence of FR-900520 under conditions which hydroxylate the C.sub.21 carbon of FR-900520. Also disclosed is a method of its use for preventing and/or counteracting accidental or inadvertent FK-506 overdosage in a therapeutic program designed to prevent in a human host, autoimmune diseases, and/or organ transplant rejections.
2. Brief Description of disclosures in the Art
In 1983, the U.S. FDA licensed cyclosporin, and extremely effective anti-rejection drug that revolutionized the field of organ transplant surgery. The drug acts by inhibiting the body's immune system from mobilizing its vast arsenal of natural protecting agents to reject the transplant's foreign protein.
As effective as the drug is in fighting transplantation rejection, it suffers drawbacks in causing kidney failure, liver damage and ulcers which in many cases can be very severe.
EPO Publication No. 0184162 to Fujisawa, hereby incorporated by reference, describes a new macrolide immunosuppressant FK-506 which is reputed to be 100 times more effective than cyclosporin. The macrolide is produced by fermentation of a particular strain of Streptomyces tsukubaensis. Also described is the closely related macrolide immunosuppressant FR-900520, produced by S. hygroscopicus subsp. yakushimaensis.
U.S. Pat. No. 3,244,592 to T. Arai describes the culturing of Streptomyces hygroscopicus var. ascomyceticus to produce the antifungal "ascomycin", which has been shown to be the same compound as FR-900520.
There is, however, no description in the literature of the production of any FK-506 type immunosuppressive agents, which substantially lack the side effects or similar side effects to cyclosporin.
Also being searched for are drugs to prevent or counteract the inadvertent or accidental overdosage effects of FK-506 or FK-506 analogs, in a therapeutic program involving FK-506 therapy.